There are several components of the research program. Component 1: Platelet Biology, Reactivity and Genomics. Utilizing one of the largest human samples (FHS: Framingham Heart Study) with platelet reactivity we have conducted deeper genetic scans for contributing genes. These scans use new genetic maps with deeper coverage of rare variation. DNA genotyping of an additional diverse population sample, the FHS OMNI cohort, was supported allowing additional validation samples and gene coverage for platelet reactivity traits. Further support was provided for genotyping of the U.K.-based Caerphilly Study in Men cohort, a rich study repository of hemostatic factor and platelet reactivity trait data. New genetic studies in 2017-18 led by the lab expanded the SNP platforms and imputation used to study platelet traits. GWAS studies in the Caerphilly study have been completed leading to new gene discoveries now being followed up in functional experiments (presented at ISTH in July 2018). An exome sequencing project using data from the FHS and the additional OMNI cohort and Caerphilly cohort data funded by our lab led to the discovery of HYAL2 as a platelet reactivity gene, along with others (Eicher et al., 2017 Thromb Haemost). The analysis of large populations for the genetics of PLT (platelet count) and MPV (mean platelet volume) resulted in the discovery of rare variation in the PLG gene that influence PLT, and D-dimer and platelet reactivity as we showed in the FHS (Mousas et al., 2017 PLoS Gen). A separate Exome Chip based study led to new discoveries in relation to platelet reactivity (Chen et al., in review). Work on WGS based analyses from the NHLBI TOPMed is nearly completed in 2018 with several new gene discoveries (being presented at ASHG 2018). Targeted qPCR RNA measurements in FHS platelet samples are also now completed and analyzed revealing novel platelet cis- and trans-eQTL results (Huffman et al., presented at ISTH 2017, manuscript in preparation). Work was supported and begun this year to conduct CRISPr-Cas9 gene editing of transgenic zebrafish to examine effects on thrombocytes and other cell populations. The candidate genes being targeted are orthologs for human genes identified in our research. A major initiative in the lab is large-scale platelet data collection in the FHS Gen3/Omni2 Exam 3. Deep data collection was started in April 2016 and data on 3,000 samples will have completed by the end of the Fiscal Year. Completion of the study is anticipated in 2019. New platelet function was initiated, led by the Lab, in 2018 in the Boston Puerto Rican Health Study in an effort to expand diverse genetic and epidemiological studies of platelet function. The Lab also expanded efforts to characterize the genetics and epidemiology of hemostatic factors which exhibit cross-talk with platelets in controlling hemostasis, coagulation, bleeding and potential disease risk. Using a Mendelian Randomization approach we provided evidence that the hemostatic factor PAI-1 is casually linked to increased risk for cardiovascular disease risk (Song et al., 2017 JAHA). Protein ELISA studies are beginning in 2018-2019 for a number of important factors including PAI-1 so they can be studied in relation to genetics and platelet function measurements. Component 2: Tissue-specific Gene Expression. A major cell- and tissue-specific database of genetic factors on gene expression (eQTLs) was maintained. This catalog was used to add information on genes to many disease and risk factor studies, primarily in the cardiovascular and metabolic disease domains. Research following up our major age-gene expression discovery paper in 15,000 humans (Peters et al., 2015 Nat Commun) was published demonstrating functional and lifespan effects in the worm C. elegans for orthologs of genes we discovered in humans (Sutphin et al., 2017 Aging Cell). Component 3: Development and Application of Bioinformatics Resources. Beyond the eQTL database mentioned above, a large genome-wide association study (GWAS) results database GRASP continues to be updated, and an online NIH query site developed. The database is publicly downloadable and queryable at the URL: grasp.nhlbi.nih.gov/Overview.aspx. One of the main changes in the database is the posting of full GWAS summary statistics where available. There are now 140 studies with such full GWAS data posted for researchers worldwide to access and utilize. The database was widely used in addressing many research questions as evidenced by thousands of web hits and queries per month and 480+ citations to GRASP-related publications.